Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia

Wei Tan, Yanhong Wang, Bert Gold, Jingshan Chen, Michael Dean, Paul J. Harrison, Daniel Weinberger, Amanda J. Law

Research output: Contribution to journalArticle

Abstract

Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants, especially rs6994992 (SNP8NRG243177). Here we have isolated and characterized full-length NRG1 type IV cDNAs from the adult and fetal human brain and identified novel splice variants of NRG1. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of ∼66 kDa. The transcript consists of 11 exons with an Ig-like domain, an epidermal growth factor-like (EGF) domain, a β-stalk, a transmembrane domain, and a cytoplasmic "a-tail," placing it in the β1a NRG1 subclass. NRG1 type IV was not detected in any tissues except brain and a putative type IV NRG1 protein of 66 kDa was similarly brain-specific. Type IV transcripts are more abundantly expressed in the fetal brain, where, in addition to the full-length structure, two novel type IV variants were identified. In vitro luciferase-reporter assays demonstrate that the 5′ promoter region upstream of type IV is functional, with differential activity associated with genetic variation at rs6994992, and that promoter competition may impact on type IV expression. Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP).

Original languageEnglish (US)
Pages (from-to)24343-24351
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number33
DOIs
StatePublished - Aug 17 2007
Externally publishedYes

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Neuregulin-1
Cloning
Molecular Cloning
Brain
Schizophrenia
Protein Isoforms
Molecular mass
Polymorphism
Luciferases
Epidermal Growth Factor
Genetic Promoter Regions
Single Nucleotide Polymorphism
Tail
Exons
Assays
Proteins
Nucleotides
Complementary DNA
Tissue
Amino Acids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. / Tan, Wei; Wang, Yanhong; Gold, Bert; Chen, Jingshan; Dean, Michael; Harrison, Paul J.; Weinberger, Daniel; Law, Amanda J.

In: Journal of Biological Chemistry, Vol. 282, No. 33, 17.08.2007, p. 24343-24351.

Research output: Contribution to journalArticle

Tan, Wei ; Wang, Yanhong ; Gold, Bert ; Chen, Jingshan ; Dean, Michael ; Harrison, Paul J. ; Weinberger, Daniel ; Law, Amanda J. / Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 33. pp. 24343-24351.
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